Multistate modeling of clinical trajectories and transition-specific risk patterns in peripheral artery disease

Background Peripheral artery disease (PAD) is characterized by heterogeneous clinical trajectories; however, long-term transitions from diagnosis to revascularization, major amputation, and death remain incompletely defined. Purpose We aimed to characterize clinical transitions in PAD using a multistate model, identify transition-specific determinants, and assess the association between early revascularization and subsequent mortality within risk strata. Methods Patients with incident PAD between 2000 and 2025 in a territory-wide multicenter cohort were included. A continuous-time multistate model was used to characterize transitions from PAD diagnosis to revascularization, major amputation, and death. State occupation probabilities were estimated, and transition-specific associations between clinical variables and each pathway were evaluated. A Cox-derived mortality risk score was categorized into tertiles for stratified analyses. IPTW-adjusted 6-month landmark analyses compared cumulative all-cause mortality between early (≤6 months) and no revascularization within 6 months across tertiles. Results A total of 22,813 patients were included (median age 77 [67–84] years; 53.9% male). Over a median follow-up of 3.3 (1.0–7.0) years, 11.1% first underwent revascularization, 6.7% first experienced major amputation, and 55.7% died without prior limb intervention. Multistate modeling demonstrated that limb events occurred predominantly early after diagnosis, whereas mortality accumulated progressively over time (Figure 1). Transition-specific analyses revealed distinct risk profiles: limb-related transitions were mainly associated with uncontrolled diabetes, tissue loss, and crural target vessel intervention, whereas mortality-related transitions were more strongly associated with older age, cardiovascular comorbidities, hypoalbuminemia, and higher neutrophil-to-lymphocyte ratio (NLR). Renal dysfunction was independently associated with both limb- and mortality-related transitions. In the 6-month landmark analysis, patients undergoing early revascularization (≤6 months) had lower 5-year cumulative mortality than those without revascularization within 6 months in the high-risk tertile (72.5% vs 78.6%; log-rank p=0.039), but not in the low- or intermediate-risk tertiles (Figure 2). Conclusion Multistate modeling delineated distinct pathways following PAD diagnosis, with limb-related transitions associated with metabolic burden and disease severity, and mortality-related transitions associated with systemic frailty, inflammation, and cardiovascular comorbidity. Renal dysfunction spanned both domains. Early revascularization was associated with lower long-term mortality in high-risk patients, suggesting the potential value of risk-stratified revascularization strategies.